226 results about "Co-stimulation" patented technology

The invention discloses an E-CAR-NK cell for treating systemic lupus erythematosus and application of the E-CAR-NK cell, and belongs to the technical field of genetic engineering.A CD19 and BCMA double-target E-CAR is adopted for modifying an NK cell, and the E-CAR-NK cell is obtained; the CD19 and BCMA double-target E-CAR is composed of the following modules: a CD8 signal peptide, a CD19 scFv, a Linker, a BCMA scFv, a CD8 Hinge region, an NKG2D transmembrane region, a CD3 epsilon signal transduction region, a DAP12 costimulatory region, a 2B4 costimulatory region, and a CD3 zeta signal transduction region. Compared with a common CAR-NK cell, the E-CAR-NK cell disclosed by the invention has higher antigen sensitivity and better continuous killing ability, so that the treatment effect of SLE is improved, and the E-CAR-NK cell has lower side effects and higher safety.

Provided is a chimeric antigen receptor targeting GCC, comprising: an scFv that specifically recognizes GCC, a CD8 hinge region or a CD28 hinge region, a CD8 transmembrane region or a CD28 transmembrane region, a CD28 co-stimulatory signal domain or a 4-1BB co-stimulatory signal domain, and a CD3ζ signal domain; the scFv that specifically recognizes GCC comprises a heavy chain variable region VH and a light chain variable region VL, the VH comprising an HC CDR1 having the amino acid sequence shown in SEQ ID NO: 1, an HC CDR2 having the amino acid sequence shown in SEQ ID NO: 2, and an HC CDR3 having the amino acid sequence shown in SEQ ID NO: 3, and the VL comprising an LC CDR1 having the amino acid sequence shown in SEQ ID NO: 4, an LC CDR2 having the amino acid sequence shown in SEQ ID NO: 5, and an LC CDR3 having the amino acid sequence shown in SEQ ID NO: 6.

The present invention is directed to a monoclonal anti-human CS1 clone 7A8D5 antibody or a single-chain variable fragment (scFv), comprising VH having the amino acid of SEQ ID NO: 4 and VL having the amino acid of SEQ ID NO: 5. The present invention is also directed to a chimeric antigen receptor fusion protein comprising from N-terminus to C-terminus: (i) CS1 scFv of the present invention, (ii) a transmembrane domain, (iii) at least one co-stimulatory domains, and (iv) an activating domain.

The invention relates to a chimeric T-cell receptor (TCR) comprising a human transmembrane domain, a human intracellular domain and a human intracellular CD3ε domain wherein in at least one of the CD3ε domains, an arginine (R) amino acid residue at position 53 and / or 54 of SEQ ID NO:25, or an arginine (R) amino acid residue at a position that corresponds to said arginine (R) amino acid residue at position 54 of SEQ ID NO:25, is substituted or deleted. The invention further relates to a method of producing a T-cell expressing the chimeric co-stimulatory TCR. The invention further relates to a chimeric T-cell receptor (TCR) comprising a human co-stimulatory domain and a human CD3ε domain. The invention further relates to a method of treating a patient having a tumor or an immune-related disease comprising administering T-cells expressing the chimeric TCR to the patient.

The present invention inter alia relates to a chimeric transmembrane receptor comprising a polypeptide, wherein the polypeptide comprises at least one T cell immunoreceptor with Ig and ITIM domains (TIGIT) polypeptide region comprising a TIGIT extracellular ligand binding domain; further wherein the polypeptide comprises at least one non-TIGIT polypeptide region, wherein the at least one non-TIGIT polypeptide region comprises a transmembrane polypeptide region of CD2, CD40, HVEM, or CD30, and wherein the at least one non-TIGIT polypeptide region comprises at least one costimulatory cytoplasmic polypeptide domain, region or motif of CD2, CD40, HVEM, or CD30, or wherein the transmembrane domain is from TIGIT and further wherein the at least one non-TIGIT polypeptide region comprises at least one costimulatory cytoplasmic polypeptide domain, region or motif of CD2 or CD28. The invention also relates to corresponding nucleic acids, vectors and T-cells comprising or expressing the chimeric receptors, to a pharmaceutical composition comprising the T-cells, and to methods for preparing a T-cell for immunotherapy and for treating a disease, respectively, wherein the chimeric transmembrane receptor is used.

The present disclosure provides a method for enhancing the anti-tumor efficacy of an Fc fusion protein which binds specifically to a target, e.g., a co-inhibitory or co-stimulatory receptor of ligand, on a T cell in a subject afflicted with a cancer or a disease caused by an infectious agent and alters the activity of the immunomodulatory target, thereby potentiating an endogenous immune response against cells of the cancer or the infectious agent, wherein the method comprises selecting, designing or modifying the Fc region of the Fc fusion protein so as to enhance the binding of said Fc region to an activating Fc receptor (FcR). The disclosure also provides an Fc fusion protein produced by said method and its use in treating a subject afflicted with a cancer or a disease caused by an infectious agent.

The present invention is directed to a humanized BCMA single-chain variable fragment (scFv), comprising VH having the amino acid sequence of SEQ ID NO: 4 and VL having the amino acid sequence of SEQ ID NO: 5. The present invention is also directed to a BCMA chimeric antigen receptor fusion protein comprising from N-terminus to C-terminus: (i) a single-chain variable fragment (scFv) of the present invention, (ii) a transmembrane domain, (iii) at least one co-stimulatory domains, and (iv) an activating domain. This humanized BCMA-CAR-T cells have specific killing activity with secretion of cytokine IFN-gamma in CAR-T cells in vitro and in vivo.

The present invention relates to multispecific antigen binding proteins that comprise an antigen-binding regions specific for a tumor-associated antigen (TAA), an antigen-binding region that specifically binds an epitope of a γδ T cell receptor (TCR), a γδ T cell-activating cytokine, and optionally, a γδ T cell co-stimulatory agonist. The γδ T cell-activating cytokine preferably is at least 5 one of an interleukin 21 receptor (IL21R) agonist and an interleukin 15 receptor (IL15R) agonist. The γδ T cell co-stimulatory agonist cytokine preferably is at least one of a 4-1BB agonist, a CD27 agonist and a GITR agonist. The multispecific antigen binding proteins of the invention specifically redirect and activate γδ T cell to lyse targeted tumor cells. The invention further relates to the use of such multispecific antigen binding proteins in the treatment of cancer, preferably a cancer 10 expressing the TAA.

The present invention provides a GD2-targeting CAR-T cell and its preparation and application. Specifically, the present invention provides a GD2-targeting CAR construct, which comprises the scFv fragment of the humanized GD2 antibody 3F8, the human Fc fragment, the ICOS transmembrane region, the ICOS and 4-1BB intracellular regions (co-stimulatory signals), and CD3ζ. The present invention also provides a CAR-T cell based on the above CAR, its preparation method and application. The CAR-T cell of the present invention can significantly inhibit the proliferation of tumor cells in a subcutaneous model of neuroblastoma, has a significant in vivo anti-tumor effect, and can be used for the targeted treatment of neuroblastoma.

Chimeric antigen receptors (CARs) and bicistronic chimeric antigen receptors (BiCisCARs) that target fibroblast growth factor receptor 4 (FGFR4), CD276, or both are disclosed. The CARs and BiCisCARs include a hinge and transmembrane domain from either CD28 or CD8 and a co-stimulatory domain from either CD28 or 4-1BB. The CARs and BiCisCARs can further include amino acid substitutions in one or more immunoreceptor tyrosine-based activation motifs (ITAMs) of a CD3ζ intracellular signaling domain. Cells expressing the CARs or BiCisCARs can be used for the treatment of cancers that express one or both of FGFR4 and CD276.

The invention relates to a CD19 and CD70 targeted double-target chimeric antigen receptor and application thereof, the CD19 and CD70 targeted double-target chimeric antigen receptor comprises an extracellular antigen binding domain, a hinge region, a transmembrane domain, an intracellular costimulatory domain and an intracellular signal transduction domain, and the extracellular antigen binding domain has specific binding ability to CD19 and CD70. The double-target chimeric antigen receptor structure has a treatment effect of targeting double antigens or single antigens, can be used for preparing immune effector cells targeting CD19 and CD70, and provides a treatment or improvement approach for diseases related to CD19 and CD70 double expression or CD19 / CD70 single expression.

The invention provides an application of a pair of immune costimulatory factors TNFSF9 / TNFRSF9 as markers in preparation of a product for early prediction of preeclampsia, and the immune costimulatory factors comprise a tumor necrosis factor superfamily member 9 (TNFSF9) and a tumor necrosis factor receptor superfamily member 9 (TNFRSF9). The product is used for carrying out early warning on the preeclampsia occurrence risk 20 weeks before pregnancy. The product is used for detecting the immune costimulatory factor through at least one of serum, plasma, whole blood and placental tissue. The invention aims to improve the early prediction efficiency of preeclampsia by detecting the abnormal expression level of the pair of markers.

The invention provides a chimeric antigen receptor for regulating and controlling a signal time sequence and application of the chimeric antigen receptor. The chimeric antigen receptor sequentially comprises a signal peptide, an extracellular domain, a transmembrane domain and an intracellular domain from an N terminal to a C terminal, the extracellular structural domain comprises an antigen recognition region and a hinge region; the intracellular domain comprises a costimulatory signal transduction region and a CD3 [zeta] intracellular region variant; the CD3 [zeta] intracellular region variant comprises three ITAMs, and the arrangement sequence of the ITAMs is ITAM3-ITAM2-ITAM1 from the N end to the C end. Compared with a conventional chimeric antigen receptor containing a wild CD3 zeta intracellular region, the chimeric antigen receptor provided by the invention can significantly enhance the functional activity of immune cells expressing the chimeric antigen receptor, which is specifically embodied in stronger multiplication capacity and durability, and significantly improves the antigen sensitivity and targeted killing efficacy.

The invention provides a spot universal CFR64-T cell prepared on the basis of CRISPR / Cas9 as well as a preparation method and application thereof. The CFR64-T cell is obtained by induced differentiation of recombinant human embryonic stem cells; in the recombinant human embryonic stem cell, a coding sequence of a CFR64 molecule is knocked into a TRAC site of the human embryonic stem cell at a fixed point through a CRISPR / Cas9 editing system; the CFR64 molecule comprises an antigen binding structural domain, a transmembrane structural domain and an intracellular costimulatory signal structural domain, the antigen binding domain is a human Fc gamma receptor extracellular domain, and the amino acid sequence of the antigen binding domain is shown in SEQ ID NO: 1. The CRISPR / Cas9 technology is adopted, gene integration sites are controllable and free of oncogene mutation risks, TCR genes are knocked out, the immunological rejection risk of universal CFR64-T cells to hosts is reduced, and meanwhile gene expression is more stable.

Provided are immunomodulatory proteins containing an engineered variant CD80 extracellular domain that exhibits improved PD-L1 binding. The immunomodulatory proteins include variant CD80 domains with amino acid substitutions in the IgV domain. Among the provided immunomodulatory proteins are variant CD80-Fc fusion proteins. Also provided are cell therapies, such as T cell therapies, engineered with secretable or transmembrane immunomodulatory proteins containing the variant CD80 disclosed herein. In some aspects, the provided immunomodulatory proteins are capable of antagonizing PD-1 / PD-L1 in addition to providing CD28 costimulation in a PD-L1-dependent fashion. Also provided are nucleic acid molecules encoding the immunomodulatory proteins. The immunomodulatory proteins provide therapeutic utility for a variety of immunological diseases, disorders, or conditions, such as cancer. Also provided are compositions and methods for making and using such immunomodulatory proteins as well as compositions and methods for making and using such cell therapies.

The present invention provides for chimeric antigen receptor constructs capable of being expressed in dendritic cells (DCs), and DCs modified to express one or more chimeric antigen receptors (CARs) as well as compositions comprising these modified DCs and methods of stimulating an adaptive immune response in a subject. The intracellular domain of the CAR comprises a toll-interleukin receptor (TIL) intracellular signalling domain and a costimulating domain selected from CD3 signalling domain, CD28 signalling domain and a combined CD28 and CD3 signalling domain.

Provided herein are novel αPD-L1 antibodies and methods of using such antibodies for the treatment of cancers. In some embodiments, the antibodies are αPD-L1×αCD28 bispecific antibodies. Such antibodies enhance anti-tumor activity by providing a costimulatory signal for T-cell activation against tumor cells while advantageously also blocking inhibitory PD-L1:PD-1 pathway interactions.

The present invention provides a long-acting dual-target chimeric antigen receptor, nucleic acid molecule, recombinant vector, cell, and application thereof. The dual-target chimeric antigen receptor comprises two independent transmembrane protein chains, wherein the first CAR chain targets a scFv of the first target, and the intracellular signal comprises a second signal and an intracellular transduction signal or only an intracellular transduction signal; the second CAR chain targets a scFv of the second target, and the intracellular signal comprises a costimulatory signal and a JAK enzyme activation transduction domain. The CAR-T cells prepared by the present invention have a strong and persistent killing effect on tumor cells that simultaneously express the first and second targets, and can be used for the anti-tumor treatment of solid tumors.

The application provides an immune cell preparation method capable of reversing tumor microenvironment immunosuppression signals and application thereof. The method for reversing the inhibitory signals is to replace the intracellular segment of a TIGIT receptor with a 4-1BB costimulatory domain and an IL-18R and a CD3 intracellular segment, and the immune cells expressing the chimeric antigen receptor recognize CD155 in a tumor microenvironment through TIGIT, avoid loss of function or exhaustion of the immune cells, and stimulate the immune cells to exert stronger tumor killing activity.

The present disclosure relates to chimeric costimulatory receptors (CCR) specific to ICAM-1, e.g., the CCRs that comprise a 4-1BB (CD137) costimulatory domain and a ICAM-1 binding domain (e.g., a ICAM-1 -specific scFv). Composition comprising such CCRs and methods of using such CCRs for preventing and treating a cancer are also provided.

The invention provides a nucleic acid construct which comprises an immune response regulatory sequence and a coding sequence of a reporter gene driven by a promoter sequence, and the immune response regulatory sequence comprises a transcription factor binding regulatory element RE which is co-stimulated and regulated by transcription factors AP-1 and CD28. The invention also provides an in-vitro immune effector function reporter gene cell model containing the nucleic acid construct, and the cell model can realize effector function activity determination performance of sensitive and potent signals so as to evaluate ADCC and ADCP killing action mechanisms and titers mediated by antibody-dependent disease cells designed by an Fc structural domain of a therapeutic antibody product. In addition, the immunosuppression and regulation efficacy of a targeted CTLA-4 or Abatacept mediated treatment method on a CD28 co-activation pathway can be evaluated.

This application provides a BCMA-targeting chimeric antigen receptor (CAR) comprising a BCMA-binding domain and an intracellular costimulatory domain derived from DAP10. Also provided are engineered immune effector cells (e.g., NK cells) containing the chimeric antigen receptor. Pharmaceutical compositions, kits, and methods for treating cancer are also provided.

The present invention discloses the application of CD40 antibody and LPS co-stimulated genetically modified B cells in the treatment of cancer, belonging to the field of biotechnology. First, the present invention discovers that B cells co-stimulated by LPS and anti-CD40 antibody can be used as cell vectors for gene therapy, continuously expressing dFv-LDP protein in vivo to treat cancer. The present invention discovers that B lymphocytes can continuously express dFv-LDP protein for a long time, solves the problem of too rapid reduction of the blood drug concentration of scFv protein to achieve a better therapeutic effect than directly injecting dFv-LDP protein, and at the same time can reduce the economic burden on patients caused by multiple injections of scFv protein.

The application discloses a chimeric antigen receptor targeting CEA and a T cell containing the chimeric antigen receptor targeting CEA. The chimeric antigen receptor is composed of a nanobody recognizing a CEA antigen, an extracellular hinge region, a transmembrane region, an intracellular signal region, a self-cleavage polypeptide T2A and a hyaluronidase in sequence. The chimeric antigen receptor can efficiently recognize the CEA antigen, and CD28 and CD137 are used as a costimulatory signal region to activate T cells, thereby playing a cellular immune role, and specifically killing CEA-positive tumor cells, and thus having an important application prospect in the field of tumor cell immunotherapy.

The invention discloses a bispecific antibody targeting T cells and Her2 positive cells and a fusion protein connected in series with 4-1BBL. Belongs to the technical field of biology. The fusion protein is of a heterotetramer structure formed by connecting two similar heavy polypeptide chains and two similar light polypeptide chains through disulfide bonds, wherein the similar heavy polypeptide chains comprise a heavy chain variable region of a Her2 targeting antibody, a human IgG1 Fc region and a human 4-1BBL extracellular region; the light polypeptide-like chain comprises a light chain variable region of a Her2 targeting antibody, a human antibody light chain constant region and a single chain variable region fragment of a CD3 targeting antibody. The fusion protein can specifically bind to Her2 positive tumor cells and CD3 molecules on the surfaces of T cells at the same time, and provides a key co-stimulation signal by using 4-1BBL connected in series, so that the killing function of the T cells is efficiently activated and enhanced in the local part of the tumor. The fusion protein provides a novel candidate strategy with stronger curative effect, more lasting effect and better safety for immunotherapy of Her2 positive tumors.

Disclosed are an artificial lymph node (aLN) comprising an extracellular matrix (ECM) hydrogel conjugated with an antigen presenting complex (Signal 1), a co-stimulatory ligand (Signal 2), and T cell-stimulating cytokine (Signal 3) and methods of their use for stimulating one or more T cells and treating a disease, disorder, or condition selected from a cancer, an infectious disease, and an autoimmune disease.

The invention discloses a chimeric antigen receptor targeting EGFRvIII and application of the chimeric antigen receptor. The chimeric antigen receptor sequentially comprises an EGFRvIII targeting nucleic acid aptamer, a transmembrane domain and an intracellular signal domain from an N end to a C end, the EGFRvIII targeted nucleic acid aptamer is an EGFRvIII specific DNA aptamer obtained on the basis of SELEX (systematic evolution of ligands by exponential enrichment) screening, can only be combined with an extracellular domain of the EGFRvIII, and is not combined with an EGFR (epidermal growth factor receptor) wild type; the intracellular signal domain comprises a costimulatory signal domain and an activation signal domain, the C end of the costimulatory signal domain is connected with the N end of the activation signal domain, and the EGFRvIII specific nucleic acid aptamer screened based on SELEX is adopted as a targeting domain, can only be specifically combined with the extracellular domain of EGFRvIII positive tumor cells, and is not subjected to cross combination with EGFR wild cells and normal cells, so that the EGFRvIII specific nucleic acid aptamer can be used for detecting EGFRvIII positive tumor cells, and the EGFRvIII specific nucleic acid aptamer can be used for detecting EGFRvIII positive tumor cells. The problem of off-target killing caused by the fact that a common antibody scFv fragment of a traditional chimeric antigen receptor (CAR) is easily combined with a wild type EGFR is fundamentally avoided.

The present invention relates to a lymphocyte comprising a recombinant nucleic acid encoding a fusion protein comprising interleukin-15 (IL-15) fused to interleukin-21 (IL-21), and optionally further comprising a recombinant antigen receptor and further optionally rendered independent of CD28 co-stimulation and resistant to exhaustion as caused by checkpoint protein expression and activation. The invention further encompasses the use of such lymphocytes, particularly in therapeutic applications such as adoptive cell therapy for cancer, autoimmune diseases, or infectious diseases. Also included within the scope of the invention are fusion proteins comprising IL-15 and IL-21 domains, nucleic acids encoding such fusion proteins, and cells—such as lymphocytes or other suitable host cells—comprising these nucleic acids.

The present invention is directed to a humanized BCMA single-chain variable fragment (scFv), comprising VH having the amino acid sequence of SEQ ID NO: 4 and VL having the amino acid sequence of SEQ ID NO: 5. The present invention is also directed to a BCMA chimeric antigen receptor fusion protein comprising from N-terminus to C-terminus: (i) a single-chain variable fragment (scFv) of the present invention, (ii) a transmembrane domain, (iii) at least one co-stimulatory domains, and (iv) an activating domain. A preferred co-stimulatory domain is CD28 or 41-BB. The humanized BCMA-CAR-T cells have specific killing activity with secretion of cytokine IFN-gamma in CAR-T cells in vitro and in vivo.

Provided herein is a composition comprising, a cell, comprising nucleic acids encoding a chimeric antigen receptor (CAR) and one or more of signaling proteins selected from K13-vFLIP, MC159-vFLIP, cFLIP-L, cFLIP-p22, HTLV1-Tax and HTLV2-Tax, wherein the CAR comprises an a) extracellular antigen specific domain, b) a transmembrane domain and c) an intracellular signaling domain comprising an immunoreceptor tyrosine-based activation motif (ITAM); wherein c) is located at the C-terminus of the chimeric receptor. In some embodiments, the CAR further comprises one or more co-stimulatory domains. Also provided herein are methods for treating diseases using the compositions described herein. Further provided herein is a kinase inhibitor for use in therapeutic methods described herein.